DESCRIPTION, OVERALL CENTER (provided by applicant): This competing renewal of our pediatric center grant will continue to focus on varying aspects of chronic kidney disease (CKD), and its sequelae, including atherosclerosis. Our Center continues to be composed of four original research projects and two cores (an administrative core, and an animal phenotyping and genotyping core), all led by the same investigators as for the last submission. The first project, led by Dr. Agnes Fogo, examines mechanisms of tubulointerstitial fibrosis, investigating the net effect of the balance of the novel sclerosis-associated molecule thymosin (34 and its anti-fibrotic metabolite, Ac-SDKP. In project 2, Dr. lekuni Ichikawa will examine the potential of podocyte proliferation and differentiation after renal injury, and the effects on renal structure and function. Dr. Valentina Kon, leading Project 3, will continue study of the role of infiltrating and resident vascular cells and accelerated atherosclerosis in CKD, and effects of angiotensin II on these processes. Project 4, led by Dr. Allison Eddy, will examine the role of novel renal tubular scavenger receptors in tubulointerstitial fibrosis, and their impact on inflammatory cell recruitment and resulting fibrosis. The Center also has three pilot and feasibility projects: Dr. Charles Alpers will examine mechanisms of innate immunity of the podocyte, focusing on the role of toll-like receptor 4 (TLR4). Dr. Jamshid Khoshnoodi will search for biomarkers of experimental diabetic nephropathy using a proteomic approach. Dr. Gilbert Moeckel will examine mechanisms of osmolyte accumulation in medullary interstitial cells, with possible consequences for fibrosis and hypertension. This team of investigators brings together novel observations supported by the last funding cycle. This strong group of projects and talented investigators, with the synergy provided by the center grant structure, will achieve a new level of understanding of CKD and its sequelae. Relevance: Chronic kidney scarring results in death unless treated with dialysis of transplantation. These studies will examine how injuries that affects the tubules or specialized cells called podocytes within the glomeruli (the filtering units of the kidney) result in scarring. Our studies will also examine the mechanisms of the greatly increased risk of hardening of the arteries, so-called atherosclerosis, that is seen in patients with chronic kidney disease.